CARDIOVASCULAR DISEASE AND STROKE (D LEIFER AND JE SAFDIEH, SECTION EDITORS)

New Evidence for Therapies in Stroke Rehabilitation

Bruce H. Dobkin & Andrew Dorsch

# Springer Science+Business Media New York 2013

Abstract Neurologic rehabilitation aims to reduce impair-ments and disabilities so that persons with serious stroke canreturn to participation in usual self-care and daily activitiesas independently as feasible. New strategies to enhancerecovery draw from a growing understanding of how typesof training, progressive task-related practice of skills, exer-cise for strengthening and fitness, neurostimulation, anddrug and biological manipulations can induce adaptationsat multiple levels of the nervous system. Recent clinicaltrials provide evidence for a range of new interventions tomanage walking, reach and grasp, aphasia, visual field loss,and hemi-inattention.

Keywords Stroke rehabilitation . Clinical trials . Robotics .

Neuroplasticity . Functional outcomes . Physical therapy

Introduction

Stroke remains a leading cause of long-term disability in theUnited States at a cost of $38 billion per year. About650,000 persons survive a new stroke yearly and 7 millionAmericans live with the complications of stroke [1]. Despiteevidence that participation in formal rehabilitative therapieslessens disability after stroke [2], less than a third receiveinpatient or outpatient therapies [3]. Of those who do accesstherapies, the frequency of use varies by geographic locationand socioeconomic status. For these patients, the amount ofrehabilitation available has progressively fallen as subacute

stroke inpatient stays have dropped to an average of lessthan 16 days and as Medicare has capped the number ofoutpatient therapy sessions to 15/year [4•]. In effect, thesedeclines in service may limit rehabilitation gains and placegreater burdens on caregivers. In contrast to these fiscallydriven realities, the science underlying stroke rehabilitationoffers new directions to improve outcomes.

Scientific advances based on animal models have sharp-ened our understanding of the genetic, molecular, physio-logic, cellular, and behavioral adaptations that drive andmay limit the recovery of function [5]. Novel types oftherapies based on manipulating mechanisms of learningand memory, neurogenesis and axonal regeneration, andneurotransmitters and growth factors can facilitate the re-covery process in models. In patients, non-invasive modal-ities including functional and structural magnetic resonanceimaging (MRI) and neuronal excitatory and inhibitory stim-ulation tools such as transcranial magnetic stimulation(TMS) are characterizing changes in connectivity betweenbrain regions after stroke [6]. Therapeutic strategies forpatients are also being drawn from engineering and comput-er science. Wireless health and communication technologieshave produced wearable sensors to remotely record thequality and quantity of walking practice, smartphone appsto cue practice, and tele-rehabilitation programs to enabletreatment in the home or community [7].

Evidence from adequately powered, randomized controltrials demonstrating the efficacy of new interventions whencompared to existing therapies has been far outpaced by thenumber of novel strategies being developed. Trials can beconfounded by the patho-anatomic and functional heteroge-neity of patients, the complexity and cost of delivering anintervention, and uncertainties regarding optimal therapytiming, dose, and duration [8]. Additionally, the outcomemeasures used in trials are often relative surrogates forpatient performance rather than direct measures of the types,quantity, and quality of physical functioning [9]. When thegoal is to assess the use of the upper extremity, walking,

This article is part of the Topical Collection on Cardiovascular Diseaseand Stroke

B. H. Dobkin (*) :A. DorschDepartment of Neurology, Geffen School of Medicine, Universityof California Los Angeles, Los Angeles, CA, USAe-mail: bdobkin@mednet.ucla.edu

A. Dorsche-mail: adorsch@mednet.ucla.edu

Curr Atheroscler Rep (2013) 15:331DOI 10.1007/s11883-013-0331-y

exercise, and participation in home and community activi-ties [10], existing measures may not fully capture clinicallyimportant changes in physical or cognitive impairments,disability, or health-related quality of life and participation[11]. Despite these confounds, recent trials do provide use-ful evidence about behavioral, pharmacologic, andneurostimulation treatments for stroke, as well as near futurehope for biological interventions for the most highly im-paired patients.

Overview of Care in Rehabilitation

Patients are admitted for inpatient stroke rehabilitation usu-ally because they are unable to walk without considerablehuman assistance and are dependent in other self-care tasks,yet have adequate memory, attention, and home support tobe able to be discharged without the need for skilled nursingplacement [12]. In the U.S., Medicare requires that patientscan tolerate at least three hours of therapist-directed treat-ment a day, usually begun within 5-10 days after onset ofstroke. Internationally, the time from stroke onset to rehabadmission is 1-6 weeks and the duration of inpatient care is3-8 weeks, but longer in Japan where a more comprehensivepost stroke care system is available [13].

The goals of inpatient therapy can include increasedindependence for self-care activities (e.g., feeding,grooming, bowel and bladder care); the ability to performsafe toilet and wheelchair transfers; walking with or withoutassistive devices such as canes and orthoses that can bracethe ankle and help control the knee; improved receptive andexpressive language skills; and better executive, visual-perceptual, working memory, and other cognitive skills. Inthe outpatient setting, patients work with therapists to refineand build upon these skills to increase their functionalindependence in the home and community [14•].

During rehabilitation, physical, occupational, and speechtherapists enable the practice of tasks of importance topatients, set and update realistic goals within the limitationsof residual reflexive and voluntary neural control, and instilla regimen of daily skills practice of progressive intensityand difficulty. Therapists may utilize neuromuscular facili-tation techniques to begin to guide the re-acquisition ofmotor skills, before building from simple to more complexactions that comprise goal-directed behaviors [15].

Principles Underlying Rehabilitative Therapies

Two basic principles influence approaches to patient treat-ment. The first is that the adult central nervous system isadaptive, or plastic, and has some capacity to re-organize itselfto recover degraded cognitive and motor functions. Animal

studies are identifying genetic and biochemical pathwaysinvolved in the establishment of new anatomic connectionsand functional network reorganization (e.g., axonal sprouting,dendrite proliferation, neurogenesis) [16•]. In patients, chang-ing patterns of brain activation appreciated by MRI and othernon-invasive imaging techniques reflect regional plasticity ofthe neuronal ensembles that represent actions and thoughts.Such changes are time-dependent and associated with learningand practice, as well as behavioral compensation for the lossof pre-stroke neural control. Thus, the brain of stroke patients,like healthy persons, constantly undergoes anatomic andphysiologic changes induced by motor learning.

The second principle is that progressive, skilled motorpractice is essential for continued gains at any time afterstroke onset. Training must engage the attention, motiva-tion, and learning networks of the brain to be effective.Better gains also depend on greater sparing of the neuralnetworks that represent the components of a behavior. Al-though observational studies suggest that maximal function-al gains are made by 3 months after onset, these studies donot account for other changes that can occur with regularpractice, such as improved walking speed and distance orgreater coordination in the use of an affected hand [17].Large, randomized controlled trials in neurologic rehabilita-tion have reported long-lasting functional improvementsafter 2-12 weeks of skilled motor practice in patients whowere weeks to years past onset of hemiparesis [18, 19••,20••]. Thus, starting at the time of initial rehabilitation,physicians ought to instill in their patients a regimen ofdaily repetitive skills practice that can be carried over intothe outpatient setting and into daily activities.

Interventions for Mobility

Fitness and Muscle Strength

Clinicians should emphasize ways for persons with stroke toaugment their general conditioning and muscle strength inboth the affected and unaffected limbs. Pre-morbiddeconditioning due to sedentary behavior exacerbates thefall-off in activity resulting from new neurologic disability[21]. Indeed, patients disabled by stroke take half as manysteps, use their affected arm much less, and have longer dailysedentary periods compared to healthy age-matched persons[22•, 23, 24]. It becomes very difficult for the hemipareticperson to achieve an aerobic effect from exercise, due to acombination of central weakness, inactivity, and muscle atro-phy [25]. This is of concern because secondary stroke preven-tion recommendations include at least a half-hour of dailyexercise rigorous enough to have at least a mild aerobic effect[26]. Just as important, higher levels of physical activity areassociated with greater neurogenesis, better performance on

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cognitive tasks, less age-related hippocampal atrophy, and areduced risk for vascular dementia.[27•, 28].

Standard rehabilitative therapies include selectivemuscle strengthening by isometric and isokinetic exer-cises to improve the power and endurance of affectedand unaffected muscle groups. Sets of moderate resis-tance exercise with weights or elastic bands are feasiblefor most patients. Simply standing up and sitting down5-10 times during commercials on television can im-prove proximal leg strength. Aerobic exercise training,whether by treadmill, over ground walking, or recum-bent cycling, can produce a conditioning effect andincrease walking speed and endurance [29]. The mostimpressive results for aerobic exercise training havebeen reported in chronic stroke patients who have re-covered sufficient motor control to participate inmoderate-to-vigorous physical activity [30••]. Questionsremain about how best to provide and reinforce aerobicexercise, such as through a support group [31], and howto maintain compliance with exercise [32]. Physicianscan encourage more frequent daily walks over longerdistances and at faster speeds in addition to more formalexercise.

Over-ground Walking and Balance Training

Over-ground gait training is an integral component ofstandard physical therapies to improve dynamic balanceand ensure safe ambulation in the home. Patients firstpractice trunk and head control, sit-to-stand balance, andthen stepping in the controlled environment of the par-allel bars. Over-ground training emphasizes clearance ofthe paretic foot to initiate leg swing, knee stability instance, and stepping with a more rhythmic, safe gaitpattern, using an assistive device or orthotic as needed.A Cochrane review found positive correlations betweenthe amount of over-ground training and small improve-ments in gait speed with no significant increase in thenumber of adverse events such as falls [33]. Falls are acommon outcome for patients recovering from stroke,with an incidence of over 40 percent for more than onefall in the first year [34]. The addition of a series ofbalance and truncal exercises, either as a supplement toinpatient therapies [35] or as part of an outpatient tele-rehabilitation intervention, [36] may prove to be a cost-effective means by which to prevent further disability.

Body Weight-supported Treadmill Training

Body weight-supported treadmill training (BWSTT) enablessupervised, repetitive, task-related practice of walking. Pa-tients with limited motor control wear a chest harnessconnected to an overhead lift to reduce the need to fully

load a paretic leg. The treadmill induces rhythmic stepping,although the paretic leg and trunk often require physicalassistance by therapists. The expectation, based on animalstudies, was that BWSTT would increase the amount ofpractice while enabling more normalized sensory inputs tobetter drive motor output for stepping. The Locomotor Ex-perience Applied Post Stroke (LEAPS) trial, however, failedto identify an additional clinical benefit of BWSTT as com-pared to a home exercise program of a similar intensity andduration [20••]. Although initially a highly regarded poten-tial intervention for poor walkers, BWSTT may not reflectthe task-related environment of over-ground training formotor learning [37•]. The cost in equipment and personnelwith the expertise to deliver BWSTT make it an interventionto be tried only for patients who have at least modest motorcontrol, but are not making progress with intensive over-ground training.

Robotic Gait Assist Devices

Electromechanical-assistive devices, including roboticsteppers and exoskeletons, provide patients with eitherfull or partial guidance of the lower limbs during thephases of the gait cycle [38]. As compared to BWSTT,for example, these devices can provide automated gaittraining on a treadmill or elliptical-like device and re-quire no hands-on supervision by therapists. To date,the devices have generally not led to greater overallgains in over-ground walking parameters than the sameintensity of more conventional physical therapy [39].Robotic devices are being introduced that may betterenable motor learning by letting patients make kinemat-ic errors during practice. Very recently, wearable, light-weight, motorized exoskeletons have become availablethat assist with hip or knee flexion and weight bearingwhile stepping over ground. Although rather expensive,they may enable slow ambulation when otherwise notfeasible; controlled studies will be needed to determineif their use can augment standard rehabilitation practice.

Functional Electrical Stimulation

FES is a technique that takes advantage of peripheral nervesand muscles left unaffected by damage to the central ner-vous system. Electrical stimulation is applied to triggercontraction and relaxation of select muscle groups. In thecase of walking, excitation of the common peroneal nerveby an externally placed stimulator results in dorsiflexion atthe ankle to aid paretic foot clearance. Small, randomizedstudies of external [40] and implanted [41] electrodeshave reported improvements in gait lasting at least sixmonths after the intervention. Though several commer-cial devices are available in the United States, efforts

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have only recently begun to demonstrate their potentialcost effectiveness [42].

Interventions for the Upper Extremity

Constraint-induced Movement Therapy and BimanualPractice

Therapy for the hemiparetic arm might begin with single-joint attempts at movement before proceeding gradually tomore complex, multi-joint actions, then task-specific prac-tice such as reaching to grasp a coffee cup, a process knownas shaping. Facilitation of skilled motor practice for theupper extremity can take several forms, including shapingplus constraint-induced movement therapy (CIMT). Thistechnique includes 6 hours a day of progressive task-related practice with restraint of the unaffected limb allday for 2 weeks. Increased use and faster skilled movementsof the affected limb may result and persist for up to twoyears [43•]. However, the intervention has shown efficacyonly in patients who can partially extend the wrist andfingers, meaning they have fair motor control and at leastmodest corticospinal tract sparing. Extensive restraint maynot be as critical to gains as the high intensity of practicewith a therapist; gains have been seen with just 2 hours ofdaily practice and without restraining the unaffected hand allday [44•, 45]. When the hand is chronically very weak,commercially available forearm-hand orthotic devices withembedded FES electrodes can enable a hand grasp or fingerpinch to assist functional use.

Bimanual practice with simultaneous arm movementsaims to activate the bilateral motor cortices and enhanceinput to the affected upper extremity, thereby leading toincreased functional use of the paretic arm and hand. Insmall trials, bimanual practice has resulted in a similardegree of functional recovery as CIMT [46•].

Mechanical Devices to Assist Arm Movements

Mechanical devices range from spring-loaded orthoticsto assist a specific movement, such as wrist extension,to fully automated, robotic limb prostheses for patient-triggered assistance of shoulder, elbow and wrist move-ments. Patients practice a series of specific joint move-ments by guiding an object on a computer screenthrough a maze. As with the electromechanical-assistive devices designed for gait training, robotic armdevices may enable more practice with more normalizedlimb kinematics. Used as a supplement to standard care,such devices may provide a benefit, [47, 48] but asimilar degree of function can usually be achieved usingstandard therapies at the same intensity [19••]. Most are

too expensive for home use. These devices may provemore efficacious in combination with other rehabilitativetherapies such as non-invasive brain stimulation, [49]but further research is needed.

Pharmacologic Therapies to Limit Spasticity

It is often not medically necessary to treat increased muscletone, unless spasms or flexor postures of the upper extremitycause pain, skin breakdown or interfere with hygiene. Bac-lofen and tizanidine are frequently used as first-line agentsand dantolene’s effects on calcium action may also reducehypertonicity. Botulinum toxin injected into selected musclegroups will reduce flexor or extensor postures around a jointfor about 3 months, but usually does not improve functionaluse of a highly paretic hand [50, 51]. Shoulder pain iscommon after hemiplegic stroke, associated with subluxa-tion and joint stresses [52]. Rapid management of pain withlight exercise, range of motion, and anti-inflammatory med-ications can help prevent pain-induced spasticity in the armand hand. Inversion and plantar flexion of the foot can alsobe lessened by medications and botulinum toxin to try toimprove stepping. When a muscle is partially paralyzed bythe toxin, daily stretching and ranging of the affected jointare necessary to maintain the improvement.

Interventions for Aphasia

Melodic Intonation and Constraint-induced Therapies

A range of individual speech and language therapytechniques have been developed to address the widevariety of aphasic syndromes that occur after stroke[53]. Most patients need a multi-modal approach tobuild on their strengths and to limit frustration in wordfinding and fluency. Melodic intonation therapy wasdeveloped for patients who have poor expression butgood comprehension. This technique uses simple melo-dies and rhythmic tapping to engage networks thatsubserve prosody of language [54]. In a nod to themassed-practice paradigm of CIMT, constraint-inducedaphasia therapy was developed as a means to improveverbal output [55]. Where comprehension is poor andoutput is perseverative, therapies have little effect. Re-gardless of the treatment modality employed, regularhome-based practice with the family is imperative forthe development of social communication.

Digital Technologies

Advances in digital communication technology have led totreatments for aphasia that can be personalized and

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delivered in the home setting [56]. For example, a recentstudy of speech entrainment that delivered an audiovisualintervention on an iPod screen reported a significant in-crease in verbal output for chronic stroke patients withBroca’s aphasia [57]. Several helpful computer programsfor home practice are also available. Treatment of speechand cognitive disorders is likely to be a growing applicationof smartphone, tele-rehab, and other Internet-enabled practiceand cueing paradigms.

Interventions for Visual Field Deficits and Inattention

Visual field loss and visual hemi-inattention degrade long-term functional outcomes in patients with stroke [58]. Whileit is unlikely that rehabilitation will result in recovery from ahemianopia, computer-based compensatory therapy may as-sist in directing visual search and attention into the area ofloss [59]. The direct dopamine agonist rotigotine modestlylessened hemispatial neglect in sub-acute stroke patients[60•]. For spatial hemi-neglect, a prism in eyeglasses willshift the center of vision toward the abnormal field toimprove reading and some self-care tasks [61].

Interventions for Locked-In Syndrome

Brain-machine interfaces utilize direct communication be-tween the nervous system and devices outside of the body toenable communication or the performance of goal-directedmovements. The devices are most needed for people withlocked-in syndrome from brainstem stroke who are withoutvoluntary control of their limbs. Alterations in the amplitudeof the mu rhythm by thoughts about an action, are recordedwith electroencephalography electrodes and interpreted by acomputer algorithm, allowing patients to select letters orwords on a computer screen for communication or to searchthe Web [62]. More advanced systems can record directlyfrom implanted microelectrodes over a variety of corticalregions. An interface then controls directional movementsof a prosthetic limb [63•]. While some of these technologiesare coming into routine use, many challenges about cost andreliability remain.

Non-invasive Brain Stimulation

In addition to being employed to study brain physiology andneuroplasticity [64], techniques including TMS and trans-cranial direct current stimulation (tDCS) have been used tomodulate cerebral plasticity in combination with physicaltraining. Most trials focus on the recovery of arm function,[65] though the techniques are being exploited to increase

verbal output in aphasia [66], improve swallowing [67], andincrease walking speed [68] to give but a few examples.Generally modest gains in aspects of motor control havebeen reported when TMS is combined with other rehabili-tative therapies [49, 69•, 70]. Similar equivocal results havebeen reported for tDCS protocols [71•]. A lack of consensuspersists regarding appropriate patient selection, stimulationprotocol, location, and duration [72]. The Food and DrugAdministration has not approved their use outside of re-search, except for some types of depression. These tech-niques seem to work best in patients who have someresidual voluntary movement.

Modulation of sensorimotor cortex excitability can alsobe achieved through the stimulation of peripheral nerves,either in isolation [73] or in conjunction with cortical stim-ulation [74] [75]. Definitive evidence that peripheral ner-vous system activation leads to improved functionaloutcomes is not yet available [76].

Mirror and Virtual Reality Therapies

The connections between parietal cortex and pre-motor andprimary motor regions can be modulated by action observa-tion and mirror therapy [77]. These techniques involvepatients watching the movements of healthy individuals or,via a mirror, the unaffected limb. The subject attempts tomimic the observed movements. In contrast to other reha-bilitative techniques such as CIMT, action observation andmirror therapy can be performed on patients with moresevere limb paresis [78]. Clinical benefit has been reportedin meta-analysis of small trials, but the magnitude of benefitdepends upon the comparator therapy provided [79].

Virtual reality (VR) therapies use technology to combineaction observation with repetitive skills practice. The hopeis that this strategy will be especially engaging and reinforcepractice paradigms. As simple as a commercially availablevideo game that can be played at home or as complex as asystem that measures joint angles in the arm and providesvisual corrective feedback, VR has generated much excite-ment in the rehabilitation community as a means to promoteand monitor skills practice [80]. Individual trials havereported benefits [81], but given the diversity of interven-tions and outcomes used, efficacy for a particular type ordegree of impairment has not yet been demonstrated [82•].

Pharmacologic Interventions

Attempts to augment stroke recovery by modulating theneurotransmitter pathways of the central nervous systemcan also involve medications. Amphetamine showed prom-ise in highly selected patients for motor gains, but no

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adequately powered trial has been completed after twentyyears of small studies [83]. Efforts to boost cerebral dopa-minergic action through the use of ropinirole proved inef-fective in patients with chronic stroke [84]. The NMDAreceptor antagonist memantine was reported to improvespontaneous speech and naming skills in chronic strokepatients with aphasia [85]. While individuals seem to occa-sionally improve in response to neurotransmitter-relateddrugs, no specific recommendations can be made.

The FLAME trial [86] tested fluoxetine in combinationwith standard rehabilitative therapies and reported betterFugl-Meyer motor scores, which tests voluntary movementsagainst gravity, for those patients who received the drug.This work needs to be replicated [87]. The drug may alsoprovide benefits as an anti-depressant, as depression affectsat least 30 % of patients within one year after stroke.

Cell-based and Biologic Therapies

Embryonic and mesenchymal stem cells, cultivated precur-sors of neurons and oligodendrocytes, and other autologousand commercialized cells are actively undergoing investiga-tion as potential treatments for stroke. Cells could replacelost neurons or glial cells, remyelinate damaged axons, orproduce substances such as growth factors that could helpdrive network function and plasticity [88]. Several reportedtrials have not reported clinical efficacy, but others are beingplanned [89, 90]. To be of value, cellular and biologicinterventions will have to be combined with applicablerehabilitation strategies to optimize their incorporation andaction in neural networks.

Off-shore stem cell clinics are all too easy to find on theInternet. These high-priced cellular interventions can have apowerful placebo effect for patients with neurologic disease.Organizations that study stem cell research policies recom-mend that no patient should participate in or pay to receive acellular intervention outside of a registered trial with aformal safety monitoring committee, in order to enablescientifically valuable information to be derived from thetrial [91, 92].

Miscellaneous Approaches

Acupuncture is frequently offered in Asian countries forstroke rehabilitation. While individual patients may report abenefit, controlled trials have generally found little or noadded value for improving specific impairments and disabil-ities [93, 94]. A recent trial reported that hyperbaric oxygentherapy may improve functional outcomes after stroke [95].The study design was less than optimal, however. The cost ofthis treatment modality is high, there are risks accompanying

its use, and the science underlying its utilization in chronicstroke is difficult to support. Etanercept, approved by the FDAfor use in psoriatic and rheumatoid arthritis, has been prof-fered as a treatment for chronic stroke in various clinics. Themanufacturer, Amgen, specifically points to a lack of evidencefor its use in stroke and the few published reports by onedermatologist are highly biased and lack proper scientifictheory, design, and interpretation of results [96].

Conclusions

Most survivors of a stroke are left with chronic disability.Rehabilitation efforts during the initial three to six monthsafter stroke should aim to maximize patients’ physical,communicative, and cognitive functioning. Continued im-provement in the chronic phase of stroke can occur withregular, progressive skills practice of goal-directed tasks inthe home [12]. Many new rehabilitation strategies, builtupon attempts to leverage technological developments toaugment the effects of practice, are opening innovativeavenues to amplify gains in performance at any time afterstroke. The future of stroke rehabilitation remains one ofpromise and challenge in treating residual disabilities, espe-cially for testing biological interventions for neural repair inthe most profoundly affected individuals.

Conflicts of Interest Bruce H. Dobkin declares that he has noconflict of interest.

Andrew Dorsch declares that he has no conflict of interest.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, et al. Heartdisease and stroke statistics-2013 update: a report from the Amer-ican Heart Association. Circulation. 2013;127(1):e6–e245.

2. Stroke Unit Trialists' Collaboration. Organised inpatient (strokeunit) care for stroke. Cochrane Database of Syst Rev. 2009 Jan21; (1): CD000197.

3. Centers for Disease Control and Prevention (CDC). Outpatientrehabilitation among stroke survivors–21 states and the Districtof Columbia, 2005. MMWR Morb Mortal Wkly Rep.2007;56:504–7.

4. • Centers for Medicare and Medicaid Services. Therapy cap. http://www.cms.gov/research-statistics-data-and-systems/monitoring-programs/medical-review/therapycap.html. Accessed 4 Mar 2013.It is remarkable how relatively few people of Medicare age areable to obtain stroke rehabilitation services.

331, Page 6 of 9 Curr Atheroscler Rep (2013) 15:331

5. Murphy TH, Corbett D. Plasticity during stroke recovery: fromsynapse to behaviour. Nat Rev Neurosci. 2009;10(12):861–72.

6. Rehme AK, Grefkes C. Cerebral network disorders after stroke:evidence from imaging-based connectivity analyses of active andresting brain states in humans. J Physiol. 2013;591(Pt 1):17–31.

7. Iosa M, Morone G, Fusco A, Bragoni M, et al. Seven capitaldevices for the future of stroke rehabilitation. Stroke Res Treat.2012;2012:187965.

8. Dobkin BH. Progressive staging of pilot studies to improve PhaseIII trials for motor interventions. Neurorehabil Neural Repair.2009;23(3):197–206.

9. Dobkin BH, Dorsch A. The promise of mHealth: daily activitymonitoring and outcome assessments by wearable sensors.Neurorehabil Neural Repair. 2011;25(9):788–98.

10. Stroke Engine. Stroke Engine-Assess. http://www.strokengine.ca/assess. Accessed 4 Mar 2013.

11. Hobart JC, Cano SJ, Zajicek JP, Thompson AJ. Rating scales asoutcome measures for clinical trials in neurology: problems, solu-tions, and recommendations. Lancet Neurol. 2007;6(12):1094–105.

12. Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl JMed. 2005;352(16):1677–84.

13. Koyama T, Sako Y, Konta M, Domen K. Poststroke dischargedestination: functional independence and sociodemographic fac-tors in urban Japan. J Stroke Cerebrovasc Dis. 2011;20(3):202–7.

14. • Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lan-cet. 2011;377(9778):1693–702. This paper reviews the most fre-quently employed interventions and the scientific basis for them.

15. Dobkin BH. The clinical science of neurologic rehabilitation. 2nded. Oxford University Press; 2004.

16. • Krakauer JW, Carmichael ST, Corbett D, Wittenberg GF. Gettingneurorehabilitation right: what can be learned from animal models?Neurorehabil Neural Repair. 2012;26(8):923–31. This reviews thelimitations and potential of animal models to enable developmentof translational neurorehabilitation strategies. Timing, dose, du-ration and intensity of a rehabilitation therapy must be determinedto optimize the strategy.

17. Ferrarello F, Baccini M, Rinaldi LA, Cavallini MC, et al. Efficacyof physiotherapy interventions late after stroke: a meta-analysis. JNeurol Neurosurg Psychiatry. 2011;82(2):136–43.

18. Wolf SL, Winstein CJ, Miller JP, Taub E, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9months after stroke: the EXCITE randomized clinical trial. JAMA.2006;296(17):2095–104.

19. •• Lo AC, Guarino PD, Richards LG, Haselkorn JK, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke.N Engl J Med. 2010;362(19):1772–83. This largest randomizedclinical trial of upper extremity robotic training versus the sameintensity of conventional therapy in highly impaired, hemipareticparticipants revealed equivalent primary outcomes, but left openthe possibility of some clinical usefulness for future studies.

20. •• Duncan PW, Sullivan KJ, Behrman AL, Azen SP, et al. Body-weight-supported treadmill rehabilitation after stroke. N Engl JMed. 2011;364(21):2026–36. This largest randomized clinicaltrial of BWSTT revealed that the experimental, highly task-oriented intervention was equivalent to home-based, progressiveexercise and balance training at the same intensity in terms ofchanges in gait speed, distance, and physical functioning, butsignificantly better than usual care starting 2 months post stroke.No differences were found between the two active interventionswhen starting BWSTT at 6 months after onset either.

21. Baert I, Daly D, Dejaeger E, Vanroy C, et al. Evolution of cardio-respiratory fitness after stroke: a 1-year follow-up study. Influenceof prestroke patients' characteristics and stroke-related factors.Arch Phys Med Rehabil. 2012;93(4):669–76.

22. • Rand D, Eng JJ, Tang PF, Jeng JS, Hung C. How active arepeople with stroke?: use of accelerometers to assess physical

activity. Stroke. 2009;40(1):163–8. Free-living physical activitywas very low in 40 subjects and 58 % of the participants did notmeet recommended physical activity levels. Use of a single com-mercial accelerometer to count steps is fairly reliable if walkingspeeds exceed 0.5m/s. Physicians might encourage longer walks athigher speeds within the limits of confidence about safety.

23. Manns PJ, Dunstan DW, Owen N, Healy GN. Addressing thenonexercise part of the activity continuum: a more realistic andachievable approach to activity programming for adults with mo-bility disability? Phys Ther. 2012;92(4):614–25.

24. Han CE, Kim S, Chen S, Lai YH, et al. Quantifying arm nonuse inindividuals poststroke. Neurorehabil Neural Repair. 2013.doi:10.1177/1545968312471904 [Epub ahead of print].

25. Billinger SA, Coughenour E, Mackay-Lyons MJ, Ivey FM. Re-duced cardiorespiratory fitness after stroke: biological conse-quences and exercise-induced adaptations. Stroke Res Treat.2012;2012:959120.

26. Furie KL, Kasner SE, Adams RJ, Albers GW, et al. Guidelines forthe prevention of stroke in patients with stroke or transient ische-mic attack: a guideline for healthcare professionals from the Amer-ican Heart Association/American Stroke Association. Stroke.2011;42(1):227–76.

27. • Voss MW, Prakash RS HS, et al. The influence of aerobic fitnesson cerebral white matter integrity and cognitive function in olderadults: Results of a one-year exercise intervention. Hum BrainMapp. 2012. doi:10.1002/hbm.22119. One of a series of smalltrials from AF Kramer and colleagues that reveals structural andfunctional connectivity improvements in the brain, as well as inseveral cognitive domains, with moderate walking exercise.

28. Verdelho A, Madureira S, Ferro JM, Baezner H, et al. Physicalactivity prevents progression for cognitive impairment and vascu-lar dementia: results from the LADIS (Leukoaraiosis and Disabil-ity) study. Stroke. 2012;43(12):3331–5.

29. Brazzelli M, Saunders DH, Greig CA, Mead GE. Physical fitnesstraining for stroke patients. Cochrane Database Syst Rev. 2011;11,CD003316.

30. •• Globas C, Becker C, Cerny J, Lam JM, et al. Chronic strokesurvivors benefit from high-intensity aerobic treadmill exercise: arandomized control trial. Neurorehabil Neural Repair.2012;26(1):85–95. Participants randomized to receive 3 months(3×/week) of progressive graded, high-intensity aerobic treadmillexercise improved significantly more than those who receivedconventional care physiotherapy in Vo2 peak, walking speed,balance and mental self-reported functioning.

31. Dean CM, Rissel C, Sherrington C, Sharkey M, et al. Exercise toenhance mobility and prevent falls after stroke: the communitystroke club randomized trial. Neurorehabil Neural Repair.2012;26(9):1046–57.

32. Touillet A, Guesdon H, Bosser G, Beis JM, Paysant J. Assessmentof compliance with prescribed activity by hemiplegic stroke pa-tients after an exercise programme and physical activity education.Arch Phys Rehabil Med. 2010;53(4):250-7–257-65.

33. States RA, Pappas E, Salem Y. Overground physical therapy gaittraining for chronic stroke patients with mobility deficits.Cochrane Database Syst Rev. 2009;3:CD006075.

34. Weerdesteyn V, de Niet M, van Duijnhoven HJ, Geurts AC. Falls inindividuals with stroke. J Rehabil Res Dev. 2008;45(8):1195–213.

35. Saeys W, Vereeck L, Truijen S, Lafosse C, et al. Randomized con-trolled trial of truncal exercises early after stroke to improve balanceand mobility. Neurorehabil Neural Repair. 2012;26(3):231–8.

36. Chumbler NR, Quigley P, Li X, Morey M, et al. Effects oftelerehabilitation on physical function and disability for strokepatients: a randomized, controlled trial. Stroke. 2012 May 24.

37. • Dobkin BH, Duncan PW. Should body weight-supported tread-mill training and robotic-assistive steppers for locomotor trainingtrot back to the starting gate? Neurorehabil Neural Repair.

Curr Atheroscler Rep (2013) 15:331 Page 7 of 9, 331

2012;26(4):308–17. A review of the pitfalls of translating animalstudies of stepping interventions into pilot studies and then phaseIII trials of robotic and treadmill-based strategies for stroke andspinal cord injury. The outcomes have generally been equivalent tothe same intensity of over-ground practice despite the theoreticalbasis for a means to better motor control.

38. Mehrholz J, Werner C, Kugler J, Pohl M. Electromechanical-assistedtraining for walking after stroke. Cochrane Database Syst Rev. 2010

39. Mehrholz J, Pohl M. Electromechanical-assisted gait training afterstroke: a systematic review comparing end-effector and exoskele-ton devices. J Rehabil Med. 2012;44(3):193–9.

40. Stein RB, Everaert DG, Thompson AK, et al. Long-term therapeu-tic and orthotic effects of a foot drop stimulator on walkingperformance in progressive and nonprogressive neurological dis-orders. Neurorehabilitation and Neural Repair. 2010;24(2):152–67.

41. Daly JJ, Zimbelman J, Roenigk KL, McCabe JP, et al. Recovery ofcoordinated gait: randomized controlled stroke trial of functionalelectrical stimulation (FES) versus no FES, with weight-supportedtreadmill and over-ground training. Neurorehabil Neural Repair.2011;25(7):588–96.

42. Taylor P, Humphreys L, Swain I. The long-term cost-effectivenessof the use of Functional Electrical Stimulation for the correction ofdropped foot due to upper motor neuron lesion. J Rehabil Med.2013;45(2):154–60.

43. • Wolf SL, Winstein CJ, Miller JP, Thompson PA, et al. Retentionof upper limb function in stroke survivors who have receivedconstraint-induced movement therapy: the EXCITE randomisedtrial. Lancet Neurol. 2008;7(1):33–40. This clinical trial, firstreported in JAMA in 2006, has continued to reveal importantinformation about the recovery of upper extremity functioning,measures of gains, and long-term consequences of the massedpractice intervention.

44. • Smania N, Gandolfi M, Paolucci S, Iosa M, et al. Reduced-intensity modified constraint-induced movement therapy versusconventional therapy for upper extremity rehabilitation afterstroke: a multicenter trial. Neurorehabil Neural Repair.2012;26(9):1035–45. Using the EXCITE trial’s entry criteria, thisrandomized trial showed that just two hours of CIMT, rather than6 hours a day for 10 days, may be more effective than conventionalrehabilitation in improving motor function and use of the pareticarm in patients with hemiparetic chronic stroke.

45. Kitago T, Liang J, Huang VS, Hayes S, et al. Improvement afterconstraint-induced movement therapy: recovery of normal motorcontrol or task-specific compensation? Neurorehabil Neural Re-pair. 2013;27(2):99–109.

46. • Wu CY, Chuang LL, Lin KC, Chen HC, Tsay PK. Randomizedtrial of distributed constraint-induced therapy versus bilateral armtraining for the rehabilitation of upper-limb motor control andfunction after stroke. Neurorehabil Neural Repair. 2011;25(2):130–9. Hemiparetic patients with chronic stroke were randomized totreatment for 2 h/d and 5 d/wk for 3 weeks to either CIMT, bimanualtraining (BAT) or a neurodevelopmental therapy approach. Out-comes were better for the first two over the latter. BAT led to modestlyhigher arm forces and CIMT to modestly greater functional ability.

47. Mann G, Taylor P, Lane R. Accelerometer-triggered electricalstimulation for reach and grasp in chronic stroke patients: a pilotstudy. Neurorehabil Neural Repair. 2011;25(8):774–80.

48. Mehrholz J, Hädrich A, Platz T, Kugler J, Pohl M. Electromechan-ical and robot-assisted arm training for improving generic activitiesof daily living, arm function, and arm muscle strength after stroke.Cochrane Database Syst Rev. 2012;6:CD006876.

49. Hesse S, Waldner A, Mehrholz J, Tomelleri C, et al. Com-bined transcranial direct current stimulation and robot-assistedarm training in subacute stroke patients: an exploratory, ran-domized multicenter trial. Neurorehabil Neural Repair.2011;25(9):838–46.

50. Shaw LC, Price CI, van Wijck FM, et al. Botulinum toxin for theupper limb after stroke (BoTULS) trial: effect on impairment,activity limitation, and pain. Stroke. 2011;42(5):1371–9.

51. Rosales RL, Kong KH, Goh KJ, Kumthornthip W, et al. Botulinumtoxin injection for hypertonicity of the upper extremity within 12weeks after stroke: a randomized controlled trial. NeurorehabilNeural Repair. 2012;26(7):812–21.

52. Blennerhassett JM, Gyngell K, Crean R. Reduced active controland passive range at the shoulder increase risk of shoulder painduring inpatient rehabilitation post-stroke: an observational study.J Physiother. 2010;56(3):195–9.

53. Brady MC, Kelly H, Godwin J, Enderby P. Speech and languagetherapy for aphasia following stroke. Cochrane Database Syst Rev.2012;5:CD000425.

54. van der Meulen I, van de Sandt-Koenderman ME, Ribbers GM.Melodic Intonation Therapy: present controversies and future op-portunities. Arch Phys Med Rehabil. 2012;93(1 Suppl):S46–52.

55. Meinzer M, Rodriguez AD, Gonzalez Rothi LJ. First decade ofresearch on constrained-induced treatment approaches for aphasiarehabilitation. Arch Phys Med Rehabil. 2012;93(1 Suppl):S35–45.

56. Cherney LR, van Vuuren S. Telerehabilitation, virtual therapists,and acquired neurologic speech and language disorders. SeminSpeech Lang. 2012;33(3):243–57.

57. Fridriksson J, Hubbard HI, Hudspeth SG, Holland AL, et al.Speech entrainment enables patients with Broca's aphasia to pro-duce fluent speech. Brain. 2012;135(Pt 12):3815–29.

58. Ali M, Hazelton C, Lyden P, Pollock A, Brady M. Recovery frompoststroke visual impairment: evidence from a clinical trials re-source. Neurorehabil Neural Repair. 2013;27(2):133–41.

59. Mödden C, Behrens M, Damke I, Eilers N, et al. A randomizedcontrolled trial comparing 2 interventions for visual field loss withstandard occupational therapy during inpatient stroke rehabilita-tion. Neurorehabil Neural Repair. 2012;26(5):463–9.

60. • Gorgoraptis N, Mah YH, Machner B, et al. The effects of thedopamine agonist rotigotine on hemispatial neglect followingstroke. Brain. 2012;135(Pt 8):2478–91. Few trials of pharmaco-logic agents have led to better outcomes after stroke.

61. Mizuno K, Tsuji T, Takebayashi T, Fujiwara T, et al. Prism adap-tation therapy enhances rehabilitation of stroke patients with uni-lateral spatial neglect: a randomized, controlled trial. NeurorehabilNeural Repair. 2011;25(8):711–20.

62. Nicolas-Alonso LF, Gomez-Gil J. Brain computer interfaces, areview. Sensors (Basel). 2012;12(2):1211–79.

63. • Hochberg LR, Bacher D, Jarosiewicz B, et al. Reach and grasp bypeople with tetraplegia using a neurally controlled robotic arm.Nature. 2012;485(7398):372–5. Two subjects with long-standingtetraplegia learned to use a neural interface system-based controlof a robotic arm to perform three-dimensional reach and graspmovements. Participants controlled the arm and hand over abroad space without explicit training, using signals decoded froma small, local population of motor cortex (MI) neurons recordedfrom an implanted 96-channel microelectrode array.

64. Dimyan MA, Cohen LG. Contribution of transcranial magneticstimulation to the understanding of functional recovery mechanismsafter stroke. Neurorehabil Neural Repair. 2010;24(2):125–35.

65. Adeyemo BO, Simis M, Macea DD, Fregni F. Systematic reviewof parameters of stimulation, clinical trial design characteristics,and motor outcomes in non-invasive brain stimulation in stroke.Front Psychiatry. 2012;3:88.

66. Naeser MA, Martin PI, Ho M, Treglia E, et al. Transcranialmagnetic stimulation and aphasia rehabilitation. Arch Phys MedRehabil. 2012;93(1 Suppl):S26–34.

67. Michou E, Mistry S, Jefferson S, Singh S, et al. Targetingunlesioned pharyngeal motor cortex improves swallowing inhealthy individuals and after dysphagic stroke. Gastroenterology.2012;142(1):29–38.

331, Page 8 of 9 Curr Atheroscler Rep (2013) 15:331

68. Wang RY, Tseng HY, Liao KK, Wang CJ, et al. rTMS combinedwith task-or iented tra ining to improve symmetry ofinterhemispheric corticomotor excitability and gait performanceafter stroke: a randomized trial. Neurorehabil Neural Repair.2012;26(3):222–30.

69. • Seniów J, Bilik M, Leśniak M, Waldowski K, et al. Transcranialmagnetic stimulation combined with physiotherapy in rehabilitationof poststroke hemiparesis: a randomized, double-blind, placebo-controlled study. Neurorehabil Neural Repair. 2012;26(9):1072–9.Repetitive TMS at 1Hz to contralesional primary motor cortex tosuppress its activity and disinhibit the lesioned side did not result ingreater upper extremity gains compared to sham stimulation. Othersmaller studies suggested modest improvements, but these may de-pend on the level of spared motor control and lesion location.

70. Talelli P, Wallace A, Dileone M, Hoad D, et al. Theta burst stimula-tion in the rehabilitation of the upper limb: a semirandomized,placebo-controlled trial in chronic stroke patients. Neurorehabil Neu-ral Repair. 2012;26(8):976–87.

71. • Lindenberg R, Renga V, Zhu LL, Nair D, Schlaug G.Bihemispheric brain stimulation facilitates motor recovery inchronic stroke patients. Neurology. 2010;75(24):2176–84. TwentyParticipants were randomly assigned to 5 consecutive sessions ofeither bihemispheric transcranial direct current stimulation toupregulate excitability of ipsilesional motor cortex anddownregulate excitability of contralesional motor cortex with si-multaneous rehabilitation or to sham stimulation with therapy.Motor function improved significantly more in the real stimulationgroup (20.7 % in Fugl-Meyer; 19.1 % in Wolf Motor Function Testscores) compared to sham (3.2 % in Fugl-Meyer; 6.0 % in Wolfscores). The effects outlasted stimulation by 1 week.

72. Hummel FC, Celnik P, Pascual-Leone A, Fregni F, et al. Contro-versy: Noninvasive and invasive cortical stimulation show efficacyin treating stroke patients. Brain Stimul. 2008;1(4):370–82.

73. Conforto AB, Ferreiro KN, Tomasi C, dos Santos RL, et al. Effectsof somatosensory stimulation on motor function after subacutestroke. Neurorehabil Neural Repair. 2010;24(3):263–72.

74. Castel-Lacanal E, Marque P, Tardy J, de Boissezon X, et al.Induction of cortical plastic changes in wrist muscles by pairedassociative stimulation in the recovery phase of stroke patients.Neurorehabil Neural Repair. 2009;23(4):366–72.

75. Celnik P, Paik NJ, Vandermeeren Y, et al. Effects of combinedperipheral nerve stimulation and brain polarization on performanceof a motor sequence task after chronic stroke. Stroke.2009;40(5):1764–71.

76. Laufer Y, Elboim-Gabyzon M. Does sensory transcutaneous electri-cal stimulation enhance motor recovery following a stroke? A sys-tematic review. Neurorehabil Neural Repair. 2011;25(9):799–809.

77. Garrison KA, Winstein CJ, Aziz-Zadeh L. The mirror neuronsystem: a neural substrate for methods in stroke rehabilitation.Neurorehabil Neural Repair. 2010;24(5):404–12.

78. Michielsen ME, Selles RW, van der Geest JN, Eckhardt M, et al.Motor recovery and cortical reorganization after mirror therapy inchronic stroke patients: a phase II randomized controlled trial.Neurorehabil Neural Repair. 2011;25(3):223–33.

79. Thieme H, Mehrholz J, Pohl M, Behrens J, Dohle C. Mirrortherapy for improving motor function after stroke. Cochrane Da-tabase Syst Rev. 2012;3:CD008449.

80. Winstein CJ, Requejo PS, Zelinski EM,Mulroy SJ, Crimmins EM. Atransformative subfield in rehabilitation science at the nexus of newtechnologies, aging, and disability. Front Psychol. 2012;3:340.

81. Subramanian SK, Lourenço CB, Chilingaryan G, Sveistrup H,Levin MF. Arm motor recovery using a virtual reality intervention

in chronic stroke: randomized control trial. Neurorehabil NeuralRepair. 2013;27(1):13–23.

82. • Saposnik G, Levin M, Outcome research Canada WorkingGroup. Virtual reality in stroke rehabilitation: a meta-analysisand implications for clinicians. Stroke. 2011;42(5):1380–6. Apooled analysis of five randomized trials, motor impairment wasdecreased by VR interventions, but no differences were found forfunctional use of the arm and hand.

83. Schuster C, Maunz G, Lutz K, Kischka U, et al. Dexamphetamineimproves upper extremity outcome during rehabilitation afterstroke: a pilot randomized controlled trial. Neurorehabil NeuralRepair. 2011;25(8):749–55.

84. Cramer SC, Dobkin BH, Noser EA, et al. Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke.Stroke. 2009;40(9):3034–8.

85. Berthier ML, Green C, Lara JP, et al. Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia. Annals ofNeurology. 2009;65(5):577–85.

86. Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recov-ery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurology. 2011;10(2):123–30. Selectivemovements (Fugl-Meyer scores) significantly improved in partici-pants with moderate motor impairment who received 20 mg offluoxetine starting 3-5 days after onset of stroke. Augmentation ofgains was hypothesized to be from modulation of mechanisms ofcerebral plasticity.

87. Mead GE, Hsieh CF, Lee R, Kutlubaev M, et al. Selective Seroto-nin Reuptake Inhibitors for Stroke Recovery: A Systematic Re-view and Meta-analysis. Stroke. 2013;44:844–50.

88. Dihné M, Hartung HP, Seitz RJ. Restoring neuronal function afterstroke by cell replacement: anatomic and functional consider-ations. Stroke. 2011;42(8):2342–50.

89. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study ofintravenous autologous mesenchymal stem cell transplantation inpatients with ischemic stroke. Stem Cells. 2010;28(6):1099–106.

90. Lindvall O, Kokaia Z. Stem cell research in stroke: how far fromthe clinic? Stroke. 2011;42(8):2369–75.

91. Hyun I, Lindvall O, Ahrlund-Richter L, Cattaneo E, et al.New ISSCR guidelines underscore major principles for re-sponsible translational stem cell research. Cell Stem Cell.2008;3(6):607–9. This working group reviews the ethical usesof cellular interventions; other societies subsequently echoedtheir recommendations.

92. Wechsler L, Steindler D, Borlongan C, Chopp M, et al. Stem CellTherapies as an Emerging Paradigm in Stroke (STEPS): bridgingbasic and clinical science for cellular and neurogenic factor therapyin treating stroke. Stroke. 2009;40(2):510–5.

93. Kong JC, Lee MS, Shin BC, Song YS, Ernst E. Acupuncture forfunctional recovery after stroke: a systematic review of sham-controlled randomized clinical trials. CMAJ. 2010;182(16):1723–9.

94. Zhuangl LX, Xu SF, D'Adamo CR, Jia C, et al. An effectivenessstudy comparing acupuncture, physiotherapy, and their combina-tion in poststroke rehabilitation: a multicentered, randomized, con-trolled clinical trial. Altern Ther Health Med. 2012;18(3):8–14.

95. Efrati S, Fishlev G, Bechor Y, Volkov O, et al. Hyperbaric oxygeninduces late neuroplasticity in post stroke patients - randomized,prospective trial. PLoS One. 2013;8(1):e53716.

96. Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuyV. Selective TNF inhibition for chronic stroke and traumatic braininjury: an observational study involving 629 consecutive patientstreated with perispinal etanercept. CNS Drugs. 2012;26(12):1051–70.

Curr Atheroscler Rep (2013) 15:331 Page 9 of 9, 331